White coat hypertension is associated with increased small vessel disease in the brain

Objective: Small vessel disease, as measured by white matter hyperintensity (WMH) in the brain, is known to be associated with increased stroke risk and cognitive impairment. This study explored the relationship between WMH on computerised tomography (CT) and white coat hypertension/effect (WCH/E) in patients with recent transient ischaemic attack (TIA) or lacunar stroke (LS). Design and method: Ninety-six patients recruited for the ASIST trial (Arterial Stiffness in Lacunar Stroke and TIA) underwent measurement of clinic blood pressure (BP) and ambulatory BP monitoring (APBM) within two weeks of TIA or LS. Twenty-three patients had normotension (clinic BP / = 140/90mmHg and day-time ABPM < 135/85mmHg). Arterial stiffness was measured using carotid-femoral pulse wave velocity (PWV) (Complior®, ALAM Medical) and carotid-ankle vascular index (CAVI) (VaSera VS-1500N®, Fukuda Denshi). CT images were scored for WMH using the four-point Fazekas visual rating scale. Patients were grouped into no-mild WMH (scores 0–1) or moderate-severe (scores 2–3) groups. The relationship between BP, vascular stiffness and WMH was explored with t-tests, chi-square and logistic regression accounting for known cardiovascular risk factors. Results: Forty-four percent of patients with WCH/E had moderate-severe WMH compared to 17% of normotensives (p = 0.047). The regression model with WMH as the dependent factor, and WCH/E and cardiovascular risk factors as independent factors showed WCH/E and either CAVI or PWV to be the only independent significant factor contributing to WMH (CAVI:p = 0.038, PWV:p = 0.043)

Musculoskeletal modelling of an ostrich (Struthio camelus) pelvic limb: influence of limb orientation on muscular capacity during locomotion

We developed a three-dimensional, biomechanical computer model of the 36 major pelvic limb muscle groups in an ostrich (Struthio camelus) to investigate muscle function in this, the largest of extant birds and model organism for many studies of locomotor mechanics, body size, anatomy and evolution. Combined with experimental data, we use this model to test two main hypotheses. We first query whether ostriches use limb orientations (joint angles) that optimize the moment-generating capacities of their muscles during walking or running. Next, we test whether ostriches use limb orientations at mid-stance that keep their extensor muscles near maximal, and flexor muscles near minimal, moment arms. Our two hypotheses relate to the control priorities that a large bipedal animal might evolve under biomechanical constraints to achieve more effective static weight support. We find that ostriches do not use limb orientations to optimize the moment-generating capacities or moment arms of their muscles. We infer that dynamic properties of muscles or tendons might be better candidates for locomotor optimization. Regardless, general principles explaining why species choose particular joint orientations during locomotion are lacking, raising the question of whether such general principles exist or if clades evolve different patterns (e.g., weighting of muscle force–length or force–velocity properties in selecting postures). This leaves theoretical studies of muscle moment arms estimated for extinct animals at an impasse until studies of extant taxa answer these questions. Finally, we compare our model’s results against those of two prior studies of ostrich limb muscle moment arms, finding general agreement for many muscles. Some flexor and extensor muscles exhibit self-stabilization patterns (posture-dependent switches between flexor/extensor action) that ostriches may use to coordinate their locomotion. However, some conspicuous areas of disagreement in our results illustrate some cautionary principles. Importantly, tendon-travel empirical measurements of muscle moment arms must be carefully designed to preserve 3D muscle geometry lest their accuracy suffer relative to that of anatomically realistic models. The dearth of accurate experimental measurements of 3D moment arms of muscles in birds leaves uncertainty regarding the relative accuracy of different modelling or experimental datasets such as in ostriches. Our model, however, provides a comprehensive set of 3D estimates of muscle actions in ostriches for the first time, emphasizing that avian limb mechanics are highly three-dimensional and complex, and how no muscles act purely in the sagittal plane. A comparative synthesis of experiments and models such as ours could provide powerful synthesis into how anatomy, mechanics and control interact during locomotion and how these interactions evolve. Such a framework could remove obstacles impeding the analysis of muscle function in extinct taxa

Synthesis and <em>In Vitro</em> Evaluation of a HER2-Specific ImmunoSCIFI Probe

Secondary Cerenkov-induced fluorescence imaging (SCIFI) is an emerging biomedical optical imaging modality that leverages Cerenkov luminescence, primarily generated by β-emitting radioisotopes, to excite fluorophores that offer near-infrared emissions with optimal tissue penetrance. Dual-functionalized immunoconjugates composed of an antibody, a near-infrared fluorophore, and a β-emitting radioisotope have potential utility as novel SCIFI constructs with high specificity for molecular biomarkers of disease. Here, we report the synthesis and characterization of [89Zr]Zr-DFO-trastuzumab-BOD665, a self-excitatory HER2-specific “immunoSCIFI” probe capable of yielding near-infrared fluorescence in situ without external excitation. The penetration depth of the SCIFI signal was measured in hemoglobin-infused optical tissue phantoms that indicated a 2.05-fold increase compared to 89Zr-generated Cerenkov luminescence. Additionally, the binding specificity of the immunoSCIFI probe for HER2 was evaluated in a cellular assay that showed significantly higher binding to SKBR3 (high HER2 expression) relative to MDA-MB-468 (low HER2) breast cancer cells based on measurements of total flux in the near-infrared region with external excitation blocked. Taken together, the results of this study indicate the potential utility of immunoSCIFI constructs for interrogation of molecular biomarkers of disease

Coherently Dedispersed Polarimetry of Millisecond Pulsars

We present a large sample of high-precision, coherently-dedispersed polarization profiles of millisecond pulsars (MSPs) at frequencies between 410 and 1414 MHz. These data include the first polarimetric observations of several of the pulsars, and the first low-frequency polarization profiles for others. Our observations support previous suggestions that the pulse shapes and polarimetry of MSPs are more complex than those of their slower relatives. An immediate conclusion is that polarimetry-based classification schemes proposed for young pulsars are of only limited use when applied to millisecond pulsars.Comment: 28 pages, 10 figures. Text matches version that appeared in ApJS. Full paper with high-resolution figures available at ftp://ftp.jb.man.ac.uk/pub/psr/papers/msppolpton.ps.g

Nonlinear Differential Equations Satisfied by Certain Classical Modular Forms

A unified treatment is given of low-weight modular forms on \Gamma_0(N), N=2,3,4, that have Eisenstein series representations. For each N, certain weight-1 forms are shown to satisfy a coupled system of nonlinear differential equations, which yields a single nonlinear third-order equation, called a generalized Chazy equation. As byproducts, a table of divisor function and theta identities is generated by means of q-expansions, and a transformation law under \Gamma_0(4) for the second complete elliptic integral is derived. More generally, it is shown how Picard-Fuchs equations of triangle subgroups of PSL(2,R) which are hypergeometric equations, yield systems of nonlinear equations for weight-1 forms, and generalized Chazy equations. Each triangle group commensurable with \Gamma(1) is treated.Comment: 40 pages, final version, accepted by Manuscripta Mathematic

Patterns of care and emergency presentations for people with non-small cell lung cancer in New South Wales, Australia: A population-based study

Introduction Little is known about population-wide emergency presentations and patterns of care for people diagnosed with non-small cell lung cancer (NSCLC) in Australia. We examined patients’ characteristics associated with presenting to an emergency department around the time of diagnosis (“emergency presenters”), and receiving anti-cancer treatment within 12 months of diagnosis. Materials and Methods Participants in the 45 and Up Study who were newly diagnosed with NSCLC during 2006–2010 were included. We used linked data from population-wide health databases including Medicare and pharmaceutical claims, inpatient hospitalisations and emergency department presentations to follow participants to June 2014. Patients’ characteristics associated with being an emergency presenter and receiving any anti-cancer treatment were examined. Results A total of 647 NSCLC cases were included (58.6% male, median age 73 years). Emergency presenters (34.5% of cases) were more likely to have a high Charlson comorbidity index score, be an ex-smoker who had quit in the past 15 years and to be diagnosed with distant metastases. Almost all patients had visited their general practitioner ≥3 times in the 6 months prior to diagnosis. Nearly one-third (29.5%) of patients did not receive any anti-cancer treatment, however, there were no differences between emergency and non-emergency presenters in the likelihood of receiving treatment. Those less likely to be treated were older, had no private health insurance, and had unknown stage disease recorded. Conclusion Our results indicate the difficulties in diagnosing lung cancer at an early stage and inequities in NSCLC treatment. Future research should address opportunities to diagnose lung cancer earlier and to optimise treatment pathways

Estimating the Cost-Effectiveness of Lung Cancer Screening with Low-Dose Computed Tomography for High-Risk Smokers in Australia

Introduction Health economic evaluations of lung cancer screening with low-dose computed tomography (LDCT) that are underpinned by clinical outcomes are relatively few. Methods We assessed the cost-effectiveness of LDCT lung screening in Australia by applying Australian cost and survival data to the outcomes observed in the U.S. National Lung Screening Trial (NLST), in which a 20% lung cancer mortality benefit was demonstrated for three rounds of annual screening among high-risk smokers age 55 to 74 years. Screening-related costs were estimated from Medicare Benefits Schedule reimbursement rates (2015), lung cancer diagnosis and treatment costs from a 2012 Australian hospital–based study, lung cancer survival rates from the New South Wales Cancer Registry (2005–2009), and other-cause mortality from Australian life tables weighted by smoking status. The health utility outcomes, screening participation rates, and lung cancer rates were those observed in the NLST. Incremental cost effectiveness ratios (ICER) were calculated for a 10-year time horizon. Results The cost-effectiveness of LDCT lung screening was estimated at AU$138,000 (80$84,700–AU$353,000)/life-year gained and AU$233,000 (80% confidence interval: AU$128,000–AU$1,110,000)/quality-adjusted life year (QALY) gained. The ICER was more favorable when LDCT screening impact on all-cause mortality was considered, even when the costs of incidental findings were also estimated in sensitivity analyses: AU$157,000/QALY gained. This can be compared to an indicative willingness-to-pay threshold in Australia of AU$30,000 to AU$50,000/QALY. Conclusions LDCT lung screening using NLST selection and implementation criteria is unlikely to be cost-effective in Australia. Future economic evaluations should consider alternative screening eligibility criteria, intervals, nodule management, the impact and cost of new therapies, investigations of incidental findings, and incorporation of smoking cessation interventions

A deep campaign to characterize the synchronous radio/X-ray mode switching of PSR B0943+10

We report on simultaneous X-ray and radio observations of the mode-switching pulsar PSR B0943+10 obtained with the XMM-Newton satellite and the LOFAR, LWA and Arecibo radio telescopes in November 2014. We confirm the synchronous X-ray/radio switching between a radio-bright (B) and a radio-quiet (Q) mode, in which the X-ray flux is a factor ~2.4 higher than in the B-mode. We discovered X-ray pulsations, with pulsed fraction of 38+/-5% (0.5-2 keV), during the B-mode, and confirm their presence in Q-mode, where the pulsed fraction increases with energy from ~20% up to ~65% at 2 keV. We found marginal evidence for an increase in the X-ray pulsed fraction during B-mode on a timescale of hours. The Q-mode X-ray spectrum requires a fit with a two-component model (either a power-law plus blackbody or the sum of two blackbodies), while the B-mode spectrum is well fit by a single blackbody (a single power-law is rejected). With a maximum likelihood analysis, we found that in Q-mode the pulsed emission has a thermal blackbody spectrum with temperature ~3.4x10^6 K and the unpulsed emission is a power-law with photon index ~2.5, while during B-mode both the pulsed and unpulsed emission can be fit by either a blackbody or a power law with similar values of temperature and photon index. A Chandra image shows no evidence for diffuse X-ray emission. These results support a scenario in which both unpulsed non-thermal emission, likely of magnetospheric origin, and pulsed thermal emission from a small polar cap (~1500 m^2) with a strong non-dipolar magnetic field (~10^{14} G), are present during both radio modes and vary in intensity in a correlated way. This is broadly consistent with the predictions of the partially screened gap model and does not necessarily imply global magnetospheric rearrangements to explain the mode switching.Comment: To be published on The Astrophysical Journa

On the multiplicativity of quantum cat maps

The quantum mechanical propagators of the linear automorphisms of the two-torus (cat maps) determine a projective unitary representation of the theta group, known as Weil's representation. We prove that there exists an appropriate choice of phases in the propagators that defines a proper representation of the theta group. We also give explicit formulae for the propagators in this representation.Comment: Revised version: proof of the main theorem simplified. 21 page

Adapting the nominal group technique for priority setting of evidence-practice gaps in implementation science

Background: There are a variety of methods for priority setting in health research but few studies have addressed how to prioritise the gaps that exist between research evidence and clinical practice. This study aimed to build a suite of robust, evidence based techniques and tools for use in implementation science projects. We applied the priority setting methodology in lung cancer care as an example. Methods: We reviewed existing techniques and tools for priority setting in health research and the criteria used to prioritise items. An expert interdisciplinary consensus group comprised of health service, cancer and nursing researchers iteratively reviewed and adapted the techniques and tools. We tested these on evidence-practice gaps identified for lung cancer. The tools were pilot tested and finalised. A brief process evaluation was conducted. Results: We based our priority setting on the Nominal Group Technique (NGT). The adapted tools included a matrix for individuals to privately rate priority gaps; the same matrix was used for group discussion and reaching consensus. An investment exercise was used to validate allocation of priorities across the gaps. We describe the NGT process, criteria and tool adaptations and process evaluation results. Conclusions: The modified NGT process, criteria and tools contribute to building a suite of methods that can be applied in prioritising evidence-practice gaps. These methods could be adapted for other health settings within the broader context of implementation science projects